rs146504767
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP3_ModerateBS2_SupportingBS1
This summary comes from the ClinGen Evidence Repository: This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of Arginine with Histidine at codon 1679 of the RYR1 protein, p.(Arg1679His). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.0022, this is considered to be more common than expected for a pathogenic variant causing autosomal dominantly inherited MHS, BS1. This variant has been reported in 2 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, 2 of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), (PMID:19346234, PMID:20142353). However, the high MAF in the NFE population in gnomAD precludes the use of PS4.This variant has been identified in an individual with negative IVCT/CHCT result, BS2_Moderate (PMID:19346234). A functional study was published for this variant using patient lymphocytes, this assay is not considered a standard assay by the ClinGen RYR1 VCEP for MHS (PMID:20142353). This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score >0.85 (0.918) supports a pathogenic status for this variant, PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Likely Benign, (PMID:29300386). Criteria implemented: BS1, BS2_Moderate, PP3_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA024479/MONDO:0007783/012
Frequency
Consequence
NM_000540.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR1 | NM_000540.3 | c.5036G>A | p.Arg1679His | missense_variant | 34/106 | ENST00000359596.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.5036G>A | p.Arg1679His | missense_variant | 34/106 | 5 | NM_000540.3 | A2 | |
RYR1 | ENST00000355481.8 | c.5036G>A | p.Arg1679His | missense_variant | 34/105 | 1 | P4 | ||
RYR1 | ENST00000599547.6 | c.5036G>A | p.Arg1679His | missense_variant, NMD_transcript_variant | 34/80 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.000946 AC: 144AN: 152202Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00113 AC: 277AN: 245716Hom.: 1 AF XY: 0.00119 AC XY: 159AN XY: 133464
GnomAD4 exome AF: 0.00130 AC: 1896AN: 1458806Hom.: 3 Cov.: 33 AF XY: 0.00127 AC XY: 922AN XY: 725896
GnomAD4 genome ? AF: 0.000945 AC: 144AN: 152320Hom.: 0 Cov.: 32 AF XY: 0.000846 AC XY: 63AN XY: 74482
ClinVar
Submissions by phenotype
Malignant hyperthermia, susceptibility to, 1 Benign:6
Likely benign, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jul 01, 2013 | - - |
Likely benign, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
Benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Likely benign, reviewed by expert panel | curation | ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen | Mar 18, 2021 | This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions. This sequence variant predicts a substitution of Arginine with Histidine at codon 1679 of the RYR1 protein, p.(Arg1679His). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.0022, this is considered to be more common than expected for a pathogenic variant causing autosomal dominantly inherited MHS, BS1. This variant has been reported in 2 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, 2 of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), (PMID:19346234, PMID:20142353). However, the high MAF in the NFE population in gnomAD precludes the use of PS4. This variant has been identified in an individual with negative IVCT/CHCT result, BS2_Moderate (PMID:19346234). A functional study was published for this variant using patient lymphocytes, this assay is not considered a standard assay by the ClinGen RYR1 VCEP for MHS (PMID:20142353). This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score >0.85 (0.918) supports a pathogenic status for this variant, PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Likely Benign, (PMID: 29300386). Criteria implemented: BS1, BS2_Moderate, PP3_Moderate. - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Aug 02, 2018 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Sep 23, 2022 | - - |
not provided Uncertain:3Benign:2
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Mar 20, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 14, 2021 | This variant is associated with the following publications: (PMID: 19346234, 23919265, 24055113, 25637381, 20142353, 25985138, 26332594, 27153395, 29441698, 24195946, 30611313, 30325262, 31517061, 21965348, 20681998, 22473935) - |
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 19, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2023 | RYR1: PP3, BS2 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 24, 2015 | - - |
not specified Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 24, 2017 | Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been reported in 5 papers, with comments suggesting VUS in relation to TAAD. It is present in gnomAD with a Max MAF of 0.13% (14/10158 Ashkenazi Jews). It is classified in ClinVar with 2 stars as VUS by Ambry and CSER_CC_NCGL. - |
Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jul 21, 2016 | - - |
Congenital multicore myopathy with external ophthalmoplegia Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Aug 02, 2018 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Central core myopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Aug 02, 2018 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
RYR1-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 27, 2024 | - - |
Malignant hyperthermia of anesthesia Benign:1
Likely benign, criteria provided, single submitter | research | CSER _CC_NCGL, University of Washington | Mar 11, 2015 | - - |
Neuromuscular disease, congenital, with uniform type 1 fiber Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at